This invention relates to a process for producing 5-aroylpyrrole compounds, particularly 5-aroylpyrrole-2-acetic acid compounds and derivatives thereof which are known in the art as having anti-inflammatory and analgesic actions.
5-Aroylpyrrole compounds and substituted 5-aroylpyrrole-2-acetic acid compounds, particularly those substituted with a lower alkyl group in the 1- and 4-positions are known in the prior art, see Carson, U.S. Pat. No. 3,752,826. A number of compounds in this class of 5-aroylpyrrole alkanoic acids and the corresponding acid derivatives thereof are taught in this patent.
U.S. Pat. No. 3,952,012 teaches the process for making a lower alkyl 5-aroyl-1-R.sub.4 -4-R.sub.5 -pyrrole-2-acetate by a process which comprises hydrolyzing a lower alkyl 1-R.sub.4 -4-R.sub.5 -3-lower alkoxy carbonyl pyrrole-2-acetate under alkaline conditions to the diacid, partially re-esterifying the pyrrole diacid to the lower alkyl 1-R.sub.4 -4-R.sub.5 -3-carboxypyrrole-2-acetate by treating the pyrrole diacid with an acidic solution of a lower alkanol, decarboxylating the 3-carboxy group of the partially re-esterified pyrrole acid ester by heating to carbon dioxide elimination temperatures and then acylating the pyrrole monoester to a lower alkyl 5-aroyl-1-R.sub.4 -4-R.sub.5 -pyrrole-2-acetate by treatment with an aroyl chloride in the presence of a Lewis Acid in an organic solvent suitable for a Friedel-Crafts acylation. The examples of U.S. Pat. No. 3,952,012 teach recovery of the desired 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid by precipitation of a solid from dilute acetic aqueous solution, collecting the precipitate, drying in vacuo and recrystallizing to obtain a white solid. This procedure requires solids handling which is difficult in large scale operations and results in losses of expensive pharmaceutical materials which is equally undesirable.
However, as shown in the prior art, because methods of producing the 1,4-dilower alkyl substituted 5-aroylpyrrole alkanoic acids involve multi-step, complex process steps, there are opportunities for impurities, degradation products and undesirable by-product materials to be present. Without specific purification steps, these undesirables may not be removed from the process and, in fact may be carried forward with the final product. Further, because the desired compounds are useful as pharmaceutical agents and intermediates therefor, it is economically and therapeutically favored to produce only the acceptable pharmaceutically efficacious agent, or intermediate therefor, and obtain that in as pure form as possible with as high a yield as possible. In many instances, the by-products are carried along with the desired 5-aroylpyrrole compounds and this presents problems of recovery and separation of the desired 1,4-dilower alkyl 5-aroylpyrrole-2-acetic acid or corresponding acid derivatives thereof.
Accordingly, one objective of the present invention is to overcome the problem of handling expensive pharmaceutical reagents as solids with the resultant losses. Another objective is to provide conversion to the desired form in a manner to minimize material losses and separate from impurities. These and other objectives will be accomplished by the process of the present invention as described in more detail hereinafter.